Combined Treatment Approach Research Articles

Inferior Overall Survival After Haploidentical Donor Lymphocyte Infusions in Relapsed Myeloid Neoplasms.

Allogeneic hematopoietic stem cell transplantation (HSCT) effectively treats high-risk myeloid neoplasms, but relapses post-HSCT, particularly in acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS), pose significant challenges. Donor lymphocyte infusion (DLI) has been utilized, but its effectiveness, especially in haploidentical settings, remains insufficiently clarified, and graft-versus-host disease (GvHD) poses a substantial risk. In this retrospective cohort study, 57 patients with AML or MDS who received DLI after allogeneic HSCT at our center from 2002 to 2023 were analyzed. Herein, only preemptively or therapeutically applied DLI were included, and endpoints included overall survival (OS), progression-free survival (PFS), and GvHD incidence post-DLI. Median OS after DLI was 517 days, with a 1-year OS of 62.5%. Factors associated with longer OS included patient age, HLA-identical donor, post-HSCT treatment naivety, and preemptive DLI indication. Haploidentical DLI was associated with inferior OS compared to HLA-identical DLI; however, PFS and GvHD incidence post-DLI did not differ significantly. Our study findings indicate that OS rate is inferior in patients with relapsed AML or MDS treated with haploidentical DLI in comparison to those who received HLA-identical DLI. Given the limitations of haploidentical DLI, alternative strategies, such as higher cell doses or combination treatment approaches, warrant further investigation.

Research progress of the SLFN family in malignant tumors

The Schlafen (SLFN) gene family has emerged as a critical subject of study in recent years, given its involvement in an array of cellular functions such as proliferation, differentiation, immune responses, viral infection inhibition, and DNA replication. Additionally, SLFN genes are linked to chemosensitivity, playing a pivotal role in treating malignant tumors. Human SLFNs comprise three domains: the N-terminal, middle (M), and C-terminal. The N- and C-terminal domains demonstrate nuclease and helicase/ATPase activities, respectively. Meanwhile, the M-domain likely functions as a linker that connects the enzymatic domains of the N- and C-terminals and may engage in interactions with other proteins. This paper aims to present a comprehensive overview of the SLFN family’s structure and sequence, examine its significance in various tumors, and explore its connection with immune infiltrating cells and immune checkpoints. The objective is to assess the potential of SLFNs as vital targets in cancer therapy and propose novel strategies for combined treatment approaches.

Optimizing the treatment of patients with intrinsic temporomandibular joint disorders

Temporomandibular joint (TMJ) dysfunctions are conditions in which there is a disruption in the anatomical and functional relationship between the various structures of the joint, including the articular disc, intra-articular ligaments, mandibular head and capsule. These disorders have a negative impact on the patient’s quality of life, resulting in limitations in masticatory function and articulation. The multifactorial nature of this pathology emphasizes the need for an individualized and comprehensive approach to the treatment of each patient. In most cases, treatment includes both surgical and orthopedic methods. Currently, combined treatment approaches aimed at synergistic effects are being actively developed to maximize therapeutic Results.The purpose of this study. To evaluate the efficacy of the combination of treatment with a repositioning mouthguard and the use of the hydraulic articular disk repositioning method in patients with internal TMJ disorders combined with dental row end defects.Materials and methods. The study included 6 patients with TMJ dysfunction and end defects of the dentition. The study was conducted between September 2023 and May 2024. As part of the study, each patient underwent cone beam computed tomography (CBCT) to evaluate the bony structures of the TMJ and ultrasound (US) to evaluate the soft tissue structures of this joint.Results. The CBCT data showed that the mean posterior temporomandibular joint displacement before treatment was 1.67, while this value increased to 3.02 after treatment. The US results showed a significant decrease in the mean value of mandibular head displacement after treatment ranging from 0.21 to 0.03, indicating a positive effect of treatment. In addition, there was a decrease in the difference in the size of the anterior and posterior parts of the articular disc, confirming the elimination of its displacement.Conclusion. The treatment combination of using a repositioning mouth guard with the hydraulic repositioning method brought about a synergistic effect on the restoration of TMJ function.

Bibliometric Analysis to Improve Combined Treatment Strategies for Glioblastoma in America

Introduction: Bibliometric analysis quantitatively examines scientific literature to extract insights. This article has conducted such analysis on glioblastoma multiforme (GBM) treatment articles. GBM, a prevalent brain tumor, is typically treated with surgery, radiation, and chemotherapy. Objectives: The article aimed to bibliometrically analyze articles discussing combined GBM treatment to identify impactful research areas and encourage collaboration. Materials and Methods: The study encompassed a comprehensive search in the Scopus database, spanning articles published from 1974 to 2022. Inclusion criteria encompassed research conducted in the Americas, both clinical and experimental. A total of 772 articles were collected and categorized based on their primary focus on combined treatment approaches. Results: Clinical studies constituted 52% of articles, suggesting a slight dominance. The analysis unveiled key research moments, including a 1998 focus shift and a pivotal 2005 study on temozolomide- radiation combination. Top journals, trends, and authors were identified, with the USA leading in contributions. Discussions: Despite high brain tumor incidence, research distribution discrepancy is concerning. Regional epidemiological studies have been endorsed. The dominance of US and German authors in GBM collaboration has raised equity issues due to budget and GDP disparities limiting Latin American representation. Conclusion: GBM research in the region is dominated by the USA, while contributions from Latin American countries remain limited. The absence of comprehensive epidemiological studies on GBM in Latin America is concerning, considering the evident impact of the disease in the region. This underscores the urgent need for increased research participation and collaboration to advance the understanding and treatment of GBM across Latin American nations.

Synergistic effects of human umbilical cord mesenchymal stem cells/neural stem cells and epidural electrical stimulation on spinal cord injury rehabilitation

Spinal cord injury (SCI) is a severe neurological condition marked by a complex pathology leading to irreversible functional loss, which current treatments fail to improve. Epidural electrical stimulation (EES) shows promise in alleviating pathological pain, regulating hemodynamic disturbances, and enhancing motor function by modulating residual interneurons in the lower spinal cord. Cell transplantation (CT), especially using human umbilical cord mesenchymal stem cells (hUCMSCs) and neural stem cells (NSCs), has significantly improved sensory and motor recovery in SCI. However, the limitations of single treatments have driven the exploration of a multifaceted strategy, combining various modalities to optimize recovery at different stages. To comprehensively investigate the effectiveness of in situ transplantation of hUCMSCs/NSCs combined with subacute epidural electrical stimulation in a murine spinal cord crush injury model, providing valuable references for future animal studies and clinical research. In this study, we first examined neural stem cell changes via mRNA sequencing in an in vitro Transwell co-culture model. We then explored cell interaction mechanisms using proliferation assays, differentiation assays, and neuron complexity analysis. For animal experiments, 40 C57BL/6 mice were assigned to four groups (Injury/EES/CT/Combination). Histological evaluations employed HE and immunofluorescence staining, while electrophysiological and behavioral tests assessed motor recovery. Quantitative data were reported as mean ± standard error, with statistical analyses performed using GraphPad Prism and SPSS. Initially, we found that NSCs in the in vitro co-culture model showed a unique expression profile of differentially expressed genes (DEGs) compared to controls. GO/KEGG analysis indicated these DEGs were mainly linked to cell differentiation and growth factor secretion pathways. Neuronal and astrocytic markers further confirmed enhanced NSC differentiation and neuronal maturation in the co-culture model. In vivo, live imaging and human nuclei immunofluorescence staining revealed that transplanted cells persisted for some time post-transplantation. Histological analysis showed that during acute inflammation, both the stem cell and combined therapy groups significantly inhibited microglial polarization. In the chronic phase, these groups reduced fibrotic scar formation and encouraged astrocytic bridging. Behavioral tests, including swimming and gait analysis, demonstrated that combined CT and EES therapy was more effective than either treatment alone. In summary, the combined therapy offers a promising approach for spinal cord injury treatment, providing superior outcomes over individual treatments. Our findings underscore the potential of a combined treatment approach utilizing stem cells transplantation and EES as an effective strategy for the comprehensive management of spinal cord crush injury in mice. This integrated approach holds promise for enhancing functional recovery and improving the quality of life for individuals with spinal cord injury (SCI).

Marginal bone resection and immediate internal fixation in multidrug resistant chronic septic nonunions of lower limb long bones: a case series.

This study aimed to evaluate the efficacy of a combined treatment approach integrating extensive debridement, immediate internal fixation, and the Masquelet technique for the management of infected nonunion of long bones in the lower limbs caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. This retrospective case series was conducted at the Imam Khomeini Hospital Complex, Tehran, Iran, a tertiary-level academic referral centre. The study documented consecutive cases of patients presenting with infected nonunion of the tibia or femur, with a positive culture for MDR or XDR bacteria, treated between January 2019 and December 2022. Inclusion criteria were adults with a confirmed diagnosis of infected nonunion due to MDR or XDR bacteria, with exclusion criteria including patients with unrelated infections or allergies to the components of the treatment regimen. The primary outcomes measured were infection resolution and bone healing. The study cohort comprised 16 patients, predominantly male (87.5%) with an average age of 38.5 years. Methicillin-resistant Staphylococcus aureus (MRSA) was identified as the causative agent in 31.25% of the infections. Patients were followed for a period ranging from 12 to 26 months. The treatment protocol was uniformly applied across all cases. Successful bone union was observed in the majority of patients within 140 to 240 days following grafting. However, there were two instances where amputation was necessitated due to the failure to eradicate the infection. Complications arose in three cases during the follow-up period: two required re-debridement due to a recurrence of the infection, and one was subjected to bone transport owing to persistent nonunion. Notably, all cases that either failed or encountered complications were smokers. In this integrated approach, high rates of infection resolution and bone healing were achieved, suggesting this method as a viable option for these complex cases.

Neoadjuvant chemoradiotherapy in combination with deep regional hyperthermia followed by surgery for rectal cancer: asystematic review and meta-analysis.

Combining chemoradiotherapy (CRT) with deep regional hyperthermia (HT) shows promise for enhancing clinical outcomes in selected rectal cancer patients. This study aimed to integrate the evidence and evaluate the efficacy of this combined treatment approach. Asystematic search of the PubMed, Scopus, and Mendeley databases was performed. This review was conducted according to the PRISMA guidelines. The quality of studies was evaluated using the Newcastle-Ottawa scale (NOS). Random-effects meta-analyses (DerSimonian and Laird) were performed. The primary outcome was pathological complete response (pCR), and secondary endpoints were overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and toxicity. In total, 12studies were included, mostly of moderate quality. Patients with locally advanced rectal cancer (LARC; n = 760) and locally recurrent rectal cancer (LRRC; n = 22) were eligible. The pooled pCR rate was 19% (95% confidence interval [CI]: 16-22%) among all 782 patients and 19% (95%CI:16-23%) among 760 LARC patients. Due to significant study heterogeneity, survival outcomes were pooled by excluding LRRC patients. The pooled 5‑year OS rate among 433 LARC patients was 87% (95%CI: 83-90%). The pooled 5‑year DFS and LRFS in LARC patients were 75% (95%CI: 70-80%) and 95% (95%CI: 92-97%), respectively. There was alack of consistent reporting of HT treatment parameters and toxicity symptoms among the studies. The collective clinical evidence showed that neoadjuvant CRT combined with HT in rectal cancer patients is feasible, with a19% pCR rate and excellent survival outcomes in long term follow-up.

Sorafenib plus memory-like natural killer cell immunochemotherapy boosts treatment response in liver cancer

BackgroundHeterogeneity of hepatocellular carcinoma (HCC) presents significant challenges for therapeutic strategies and necessitates combinatorial treatment approaches to counteract suppressive behavior of tumor microenvironment and achieve improved outcomes. Here, we employed cytokines to induce memory-like behavior in natural killer (NK) cells, thereby enhancing their cytotoxicity against HCC. Additionally, we evaluated the potential benefits of combining sorafenib with this newly developed memory-like NK cell (pNK) immunochemotherapy in a preclinical model.MethodsHCC tumors were grown in SD rats using subcapsular implantation. Interleukin 12/18 cytokines were supplemented to NK cells to enhance cytotoxicity through memory activation. Tumors were diagnosed using MRI, and animals were randomly assigned to control, pNK immunotherapy, sorafenib chemotherapy, or combination therapy groups. NK cells were delivered locally via the gastrointestinal tract, while sorafenib was administered systemically. Therapeutic responses were monitored with weekly multi-parametric MRI scans over three weeks. Afterward, tumor tissues were harvested for histopathological analysis. Structural and functional changes in tumors were evaluated by analyzing MRI and histopathology data using ANOVA and pairwise T-test analyses.ResultsThe tumors were allowed to grow for six days post-cell implantation before treatment commenced. At baseline, tumor diameter averaged 5.27 mm without significant difference between groups (p = 0.16). Both sorafenib and combination therapy imposed greater burden on tumor dimensions compared to immunotherapy alone in the first week. By the second week of treatment, combination therapy had markedly expanded its therapeutic efficacy, resulting in the most significant tumor regression observed (6.05 ± 1.99 vs. 13.99 ± 8.01 mm). Histological analysis demonstrated significantly improved cell destruction in the tumor microenvironment associated with combination treatment (63.79%). Interestingly, we observed fewer viable tumor regions in the sorafenib group (38.9%) compared to the immunotherapy group (45.6%). Notably, there was a significantly higher presence of NK cells in the tumor microenvironment with combination therapy (34.79%) compared to other groups (ranging from 2.21 to 26.50%). Although the tumor sizes in the monotherapy groups were similar, histological analysis revealed a stronger response in pNK cell immunotherapy group compared to the sorafenib group.ConclusionsExperimental results indicated that combination therapy significantly enhanced treatment response, resulting in substantial tumor growth reduction in alignment with histological analysis.

Attention Deficit Hyperactivity Disorder among Children with Speech Difficulties

Abstract: Speech sound disorders and attention deficit / hyperactivity disorder are developmental disorders that can significantly impact academic success. The comorbidity of these disorders may substantially add to the difficulties experienced by the child and require a combined treatment approach. Objectives: (1) to assess sociodemographic characteristics of children’s with speech difficulties (2) to assess attention deficit hyperactivity disorder and speech difficulties (3) to identify the relationship between attention deficit hyperactivity disorder and speech difficulties. Methodology: A descriptive cross-sectional study design was carried out in Baghdad Teaching Hospital. A non- probability (purposive) study sample of (300) child, who attended Hearing and Speech Center for the period from 12/April/2023 to 25/January/2024. The Questionnaire which is composed of: Socio-demographic characteristics, scales of behavioral problem, attention deficit hyperactivity disorder. Results: The study results reveal that the children experiencing severe attention deficit hyperactivity disorder and that significant relationship have been reported among speech sound disorder with attention deficit hyperactivity disorder at p-values= 0.046, also indicates that there was significant relationship among childhood apraxia and attention deficit hyperactivity disorder at p-values= 0.007. Conclusion: The children experience severe of attention deficit hyperactivity disorder, the significant relationship has been reported among speech sound disorder with attention deficit hyperactivity disorder, also indicates that there was significant relationship among childhood apraxia and attention deficit hyperactivity disorder.Recommendations: An intervention program to be planned accordingly and areas of deficit will be targeted in therapy. Liaison with parents and school teachers is indicated in order to achieve the child’s maximum potential.

Platelet-Rich Plasma Therapy for Rotator Cuff Injuries: A Comprehensive Review of Current Evidence and Future Directions.

Rotator cuff injuries are a prevalent cause of shoulder pain and disability, significantly impacting daily activities and quality of life. Platelet-rich plasma (PRP) therapy has emerged as a potential treatment for these injuries, aiming to enhance healing by delivering concentrated platelets and growth factors. This review comprehensively evaluates the current evidence regarding PRP therapy for rotator cuff injuries. It examines clinical trial data, comparing PRP therapy with conventional treatments such as physical therapy and surgical intervention. The review also explores the biological mechanisms of PRP, including its role in promoting tendon repair and regeneration through growth factors and cytokines. In addition, it addresses variables that may affect PRP therapy outcomes, including preparation techniques, injection methods, and patient-specific factors. The review highlights the need for standardized protocols and further research to optimize PRP therapy and address existing gaps in knowledge. Future directions include exploring combined treatment approaches and assessing long-term outcomes to refine PRP therapy's role in rotator cuff injury management. This review aims to provide valuable insights into the effectiveness of PRP therapy, contributing to improved treatment strategies and enhanced patient outcomes.

Control of Hepatitis B Virus with Imdusiran, a Small Interfering RNA Therapeutic.

Chronic hepatitis B is a global health concern with a high risk of end-stage liver disease. Current standard-of-care agents have low cure rates, and new therapies are needed. Small interfering RNAs (siRNAs) that target viral RNAs fulfill a gap not addressed by standard-of-care agents and may contribute to a functional cure. Here, we describe the preclinical characterization of imdusiran (AB-729), a novel, pan-genotypic siRNA therapeutic that effectively reduces HBsAg, viral antigens, and viral replication in chronic hepatitis B patients and is currently in Phase 2 clinical studies. In hepatitis B virus (HBV) cell-based systems, imdusiran possessed pan-genotypic nanomolar potency and retained activity against HBV target site polymorphisms. Imdusiran was active against nucleos(t)ide analogue- and capsid assembly modulator-resistant HBV isolates, and combination with standard-of-care agents was additive. In an HBV adeno-associated virus mouse model, HBsAg was reduced up to 3.7 log10 after a single imdusiran dose, with sustained suppression for 10 weeks. Imdusiran did not intrinsically stimulate cytokine release in healthy donor human whole blood, supportive of its mechanism of action as a direct acting RNA interference antiviral. Taken together, these data support imdusiran in combination treatment approaches toward chronic hepatitis B functional cure.

International expert opinion on the considerations for combining vosoritide and limb surgery: a modified delphi study

BackgroundAchondroplasia is the most common form of skeletal disorder with disproportionate short stature. Vosoritide is the first disease-specific, precision pharmacotherapy to increase growth velocity in children with achondroplasia. Limb surgery is a standard approach to increase height and arm span, improve proportionality and functionality, as well as correcting deformities. The aim of this study was to gain expert opinion on the combined use of vosoritide and limb surgery in children and adolescents with achondroplasia.MethodsAn international expert panel of 17 clinicians and orthopaedic surgeons was convened, and a modified Delphi process undertaken. The panel reviewed 120 statements for wording, removed any unnecessary statements, and added any that they felt were missing. There were 26 statements identified as facts that were not included in subsequent rounds of voting. A total of 97 statements were rated on a ten-point scale where 1 was ‘Completely disagree’ and 10 ‘Completely agree’. A score of ≥ 7 was identified as agreement, and ≤ 4 as disagreement. All experts who scored a statement ≤ 4 were invited to provide comments.ResultsThere was 100% agreement with several statements including, “Achieve a target height, arm span or upper limb length to improve daily activities” (mean level of agreement [LoA] 9.47, range 8–10), the “Involvement of a multidisciplinary team in a specialist centre to follow up the patient” (mean LoA 9.67, range 7–10), “Planning a treatment strategy based on age and pubertal stage” (mean LoA 9.60, range 8–10), and “Identification of short- and long-term goals, based on individualised treatment planning” (mean LoA 9.27, range 7–10), among others. The sequence of a combined approach and potential impact on the physes caused disagreement, largely due to a lack of available data.ConclusionsIt is clear from the range of responses that this modified Delphi process is only the beginning of new considerations, now that a medical therapy for achondroplasia is available. Until data on a combined treatment approach are available, sharing expert opinion is a vital way of providing support and guidance to the clinical community.

Depression with comorbid juvenile-onset fibromyalgia syndrome novel treatment plan using interpersonal psychotherapy: A case report.

Fibromyalgia syndrome (FMS) affects 2% to 4% of people, with increasing prevalence in Saudi Arabia reaching 13.4%. FMS can occur in adolescents, known as juvenile-onset fibromyalgia (JFM) with comorbidities including depression, anxiety, and psychological stress. Our patient presented to the child and adolescent psychiatry clinic at King Saud University Hospital Medical City. A year before coming to our clinic, at the age of 15 she was initially diagnosed with JFM followed by a comorbid persistent depressive disorder. As a novel treatment method, a combination treatment approach was used, including a pharmacological intervention with Duloxetine, and a non-pharmacological intervention with interpersonal psychotherapy for adolescents. She completed 16 weeks of therapy while monitoring for duloxetine response and side effects. Depressive symptoms were in remission by treatment's end and continued to be in her first month posttreatment follow-up, and the FMS symptoms were also controlled. Our present case highlights a combined approach to treat depression and JFM in adolescents as a novel intervention method thus we strongly recommend utilizing it for similar cases.

Comparison of the Efficacy of Transcatheter Arterial Chemoembolization Combined with Radiofrequency Ablation Versus Monotherapy in Patients with Liver Cancer.

This study assesses the effectiveness of combining transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) in treating hepatocellular carcinoma (HCC). Retrospective analysis of 125 HCC patients treated from 2020 to 2021, divided into two groups: monotherapy using TACE (n = 63), and a combined approach of RFA and TACE (n = 62). Comparison factors included clinical efficacy, liver function, tumor markers, complications, quality of life, and prognosis. The combined treatment group showed higher effectiveness (p < 0.05), improved liver function and tumor marker levels 4 weeks post-treatment (p < 0.05), significantly fewer complications (p < 0.05), and enhanced quality of life at the year-long follow-up (p < 0.05). The prognosis was better in the combination group, demonstrated by fewer recurrences and higher 1-year survival rates (p < 0.05). The dual approach of TACE and RFA shows improved results for HCC patients, including improved liver function, reduced tumor markers, fewer complications, and superior quality of life and prognosis. Consequently, combined treatment approach is endorsed for clinical practice.

Large deformation problems arising from deep excavation in silt strata: A case study in Shenzhen, China

Deep excavations in silt strata can lead to large deformation problems, posing risks to both the excavation and adjacent structures. This study combines field monitoring with numerical simulation to investigate the underlying mechanisms and key aspects associated with large deformation problems induced by deep excavation in silt strata in Shenzhen, China. The monitoring results reveal that, due to the weak property and creep effect of the silt strata, the maximum wall deflection in the first excavated section (Section 1) exceeds its controlled value at more than 93% of measurement points, reaching a peak value of 137.46 mm. Notably, the deformation exhibits prolonged development characteristics, with the diaphragm wall deflections contributing to 39% of the overall deformation magnitude during the construction of the base slab. Subsequently, numerical simulations are carried out to analyze and assess the primary factors influencing excavation-induced deformations, following the observation of large deformations. The simulations indicate that the low strength of the silt soil is a pivotal factor that results in significant deformations. Furthermore, the flexural stiffness of the diaphragm walls exerts a notable influence on the development of deformations. To address these concerns, an optimization study of potential treatment measures was performed during the subsequent excavation of Section 2. The combined treatment approach, which comprises the reinforcement of the silt layer within the excavation and the increase in the thickness of the diaphragm walls, has been demonstrated to offer an economically superior solution for the handling of thick silt strata. This approach has the effect of reducing the lateral wall displacement by 83.1% and the ground settlement by 70.8%, thereby ensuring the safe construction of the deep excavation.

Stereotactic Radiosurgery With Versus Without Neoadjuvant Endovascular Embolization for Brain Arteriovenous Malformations With Associated Intracranial Aneurysms.

Stereotactic radiosurgery (SRS) with neoadjuvant embolization is a treatment strategy for brain arteriovenous malformations (AVMs), especially for those with large nidal volume or concomitant aneurysms. The aim of this study was to assess the effects of pre-SRS embolization in AVMs with an associated intracranial aneurysm (IA). The International Radiosurgery Research Foundation AVM database from 1987 to 2018 was retrospectively reviewed. SRS-treated AVMs with IAs were included. Patients were categorized into those treated with upfront embolization (E + SRS) vs stand-alone SRS (SRS). Primary end point was a favorable outcome (AVM obliteration + no permanent radiation-induced changes or post-SRS hemorrhage). Secondary outcomes included AVM obliteration, mortality, follow-up modified Rankin Scale, post-SRS hemorrhage, and radiation-induced changes. Forty four AVM patients with associated IAs were included, of which 23 (52.3%) underwent pre-SRS embolization and 21 (47.7%) SRS only. Significant differences between the E + SRS vs SRS groups were found for AVM maximum diameter (1.5 ± 0.5 vs 1.1 ± 0.4 cm3, P = .019) and SRS treatment volume (9.3 ± 8.3 vs 4.3 ± 3.3 cm3, P = .025). A favorable outcome was achieved in 45.4% of patients in the E + SRS group and 38.1% in the SRS group (P = .625). Obliteration rates were comparable (56.5% for E + SRS vs 47.6% for SRS, P = .555), whereas a higher mortality rate was found in the SRS group (19.1% vs 0%, P = .048). After adjusting for AVM maximum diameter, SRS treatment volume, and maximum radiation dose, the likelihood of achieving favorable outcome and AVM obliteration did not differ between groups (P = .475 and P = .820, respectively). The likelihood of a favorable outcome and AVM obliteration after SRS with neoadjuvant embolization in AVMs with concomitant IA seems to be comparable with stand-alone SRS, even after adjusting for AVM volume and SRS maximum dose. However, the increased mortality among the stand-alone SRS group and relatively low risk of embolization-related complications suggest that these patients may benefit from a combined treatment approach.

Toxicity profile of camrelizumab-based immunotherapy in older adults with advanced cancer

Immune checkpoint inhibitors (ICIs) have become an important cornerstone of many tumour treatments. However, the toxicity profile of immune-chemotherapy combination treatment approaches among older adult cancer patients is still unclear. Patients with any cancer who received camrelizumab-based immunotherapy were eligible for inclusion. The primary endpoints were adverse events (AEs) and immune-related adverse events (irAEs), which were defined based on Naranjo's algorithm. Patients were stratified by age (≥ 70 years and < 70 years), and comparisons were made based on the type of camrelizumab-based therapy (monotherapy, combined chemotherapy, or combined anti-VEGF therapy). A total of 185 patients were administered camrelizumab-based immunotherapy, 55 (30%) of whom were ≥ 70 years old. A total of 146 (78.9%) patients received camrelizumab-based combination treatment. The incidence of all-grade AEs was 56.8% (105 patients), while that of irAEs was 36.8% (68 patients). There was no difference in the percentage of patients experiencing any grade or grade ≥ 3 AEs between age groups. However, the frequency of irAEs (both any grade and grade ≥ 3) significantly differed by age group (P = 0.001 and 0.009, respectively). The results of multivariable analysis revealed that age ≥ 70 years was the only independent risk factor for irAEs. The results of subgroup analysis revealed that the incidence of irAEs was higher in older patients treated with camrelizumab-chemotherapy, while the incidence rates were similar between age groups in the monotherapy and combination anti-VEGF treatment subgroups. Immune-related diabetes mellitus occurred more frequently among older adults. The spectrum of irAEs showed that combination immunotherapy had more widely effects on the organ system than monotherapy. In this study, older (≥ 70 years) patients had a higher risk of all-grade and high-grade irAEs when receiving camrelizumab chemotherapy combination treatment. Notably, long-term random glucose monitoring should be performed during ICI-based immunotherapy in older cancer patients.

Reduced Efficacy of Behavior Therapy Following Initial Multimodal Treatment of ADHD

ABSTRACT Background Evidence-based treatments for childhood attention-deficit/hyperactivity disorder (ADHD) include behavioral treatment and psychostimulants, preferably in combination. Research on the treatment of ADHD underscores a gap in the literature regarding the optimal sequencing of treatments (Pelham et al. 2020). Emerging evidence supports starting with behavioral treatment before psychostimulants, though the mechanisms of this sequencing effect are not entirely understood. Objective This study explores one plausible mechanism – that psychostimulants reduce behaviors targeted by behavioral treatment, thereby reducing opportunities for children to learn and practice self-regulation skills. The article reports post hoc findings from a triple-masked, AB/BA crossover study, conducted in the Summer Treatment Program (STP). Method Two-hundred forty-eight children diagnosed with ADHD; 77% male; 85% Hispanic) were randomized to receive either (a) intensive behavior therapy plus medication (“COMB”) or (b) intensive behavior therapy plus placebo (“BT”) for 3 weeks, then crossed over to the other condition for 3 weeks. Behavior in recreational settings was systematically recorded and analyzed as a function of medication status and order of treatments. Results We found evidence that initial medication reduced the efficacy of subsequent behavior therapy. That is, children exhibited significantly more misbehaviors when unmedicated if they started with combined treatment, then had medication withdrawn, than if they started with behavior therapy alone. Conclusion These findings suggest that starting with a combined treatment approach had an unintended adverse impact on children’s behavioral functioning when medication was withdrawn. The results support current clinical recommendations, which are to start treatment of ADHD with behavior therapy alone and to add medication as necessary.

Melatonin and copper oxide nanoparticles synergistically mitigate clubroot disease and enhance growth dynamics in Brassica rapa

Clubroot, a devastating soil borne disease affecting 30%∼50% of Brassicaceae crops worldwide, lacks effective control measures. In the present study, we explored the potential of melatonin (MT) and copper oxide nanoparticle (CuO-NPs) in mitigating clubroot severity in the Brassica rapa ssp. pekinensis. Following 18 h priming with MT, CuO-NPs, or both seeds were grown in controlled environment using synthetic potting mix. Inoculated with Plasmodiophora brassicae spores on 5th day, followed by a soil drench phyto-nano treatment with a week interval. Plants were assessed for various health and growth indices including disease, biometrics, photosynthesis, reactive oxygen species (ROS), antioxidant enzyme activity, hormones and genes expression at onset of secondary clubroot infection using established protocols. Statistical analysis employed ANOVA with Fisher's LSD for significance assessment (P < 0.05). Our results revealed that seed priming with both MT (50 μMol/L) and CuO-NPs (200 mg/L), followed by soil drenching significantly reduced clubroot incidence (38%) and disease index (57%), compared to control treatments. This synergistic effect was associated with enhanced plant growth (shoots: 48% and roots: 59%). Plants treated with both MT and CuO-NPs showed robust antioxidant defenses, significantly increased superoxide dismutase (SOD (25/29%)), catalase (CAT (83/55%)), and ascorbate peroxidase (APX (83/46%)) activity in both shoots/roots, respectively, compared to infected control. Notably, salicylic acid and jasmonic acid levels doubled in treated plants, while stress hormone abscisic acid (ABA) decreased by 80% in roots and 21% in shoots. Gene expression analysis corroborated these findings, showing that the combined treatment activated antioxidant defense genes (SOD, APX and CAT) by 1.9–7.2-fold and upregulated hormone signaling genes JAZ1 (7.8-fold), MYC2 (3.9-fold) and SABP2 (36-fold). Conversely, ABA biosynthesis genes (ABA1 and NCED1) were downregulated up to 7.2-fold, while plant resistance genes NPR1, PRB1 and PDF1.2 were dramatically increased by up to 6.3-fold compared to infected plants. Overall, our combined treatment approach significantly reduces clubroot severity in B. rapa via enhanced antioxidant defenses, improved ROS scavenging, coordinated hormonal regulation and increased pathogen response genes. This study offers promising strategy for developing effective control measures against clubroot in susceptible cruciferous crops.

Low-dose intravitreal injection of 4 mg preservative-free gentamicin and superficial lamellar keratectomy combined with modified Gundersen grafts to control chronic heterochromic iridocyclitis and secondary keratitis in horses.

To describe a combined treatment approach for heterochromic iridocyclitis and secondary keratitis (HIK) in horses. A total of 15 horses (16 eyes). Sixteen eyes from 15 horses (mean age 14.1 years, range 6-26 years) received low-dose (4 mg) intravitreal preservative-free gentamicin injection (IVGI) and modified Gundersen grafts with standing sedation and local anesthesia following a clinical diagnosis of HIK. Additional therapies of suprachoroidal triamcinolone (8 mg) injection, episcleral bromfenac implants, and suprachoroidal cyclosporine implants were performed in individual cases. Leptospira titers were also reported when available. The most frequent ophthalmic findings were pigmented keratic precipitates (n = 15/16 eyes, 94%), corneal edema (n = 14/16 eyes, 88%), and pigmented cells suspended in the anterior chamber (n = 7/16 eyes, 44%). Postoperative treatment generally consisted of topical and systemic NSAIDs, topical antibiotics, and a topical mydriatic agent. Complications included persistent corneal edema (7/16, 44%), corneal ulceration (6/16, 38%), graft failure requiring revision (2/16, 13%), stromal abscess (1/16, 6%), surgery site infection (1/16, 6%), and suspected retinal degeneration following IVGI (1/16, 6%). One case was enucleated 6 months after treatment (1/16, 6%). Of the 12 eyes with at least 3 months of post-treatment follow-up, 10 were comfortable and visual with static or improved symptoms of HIK. This multimodal treatment approach aims to address both the anterior uveitis and endothelial decompensation frequently seen in horses with HIK. The surgery can be performed under standing sedation. Continued evaluation and long-term follow-up is necessary in all horses with HIK.